6,7-Dihalo-Benzothiadiazines as Potent and Selective AMPA Receptor Modulators for Cognitive Enhancement and Neuroprotection

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are tetrameric ionotropic glutamate receptors that mediate fast excitatory synaptic transmission in the brain and represent important therapeutic targets for neurological disorders. Positive allosteric modulators (PAMs) of AMPA receptors enhance rapid excitatory signaling by increasing receptor's sensitivity to glutamate and have been widely explored as agents to improve cognitive function in central nervous system (CNS) diseases. Structural modification of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) analogs is a key strategy to develop potent AMPAR PAMs. A recent study reported a new pharmacomodulation strategy on the benzene ring of BTDs through systematic structure-activity relationship (SAR) optimization. This work led to the identification of compound <b>14o</b> (BPAM363), which exhibits improved pharmacological properties, robust <i>in vivo</i> cognitive-enhancing and neuroprotective effects. These findings provide valuable insight for further development of AMPAR PAMs as therapeutic candidates for cognitive disorders.